DESCRIPTION Abstract We are interested in understanding how the brain generates social attachments. Humans form enduring social relationships that shape the rules for interacting with other individuals. Ruptured social ties are often the first sign of mental illness, and are usually the most difficult to heal. Even in healthy individuals, breakdown of a social relationship such as marriage leads to a dramatic increase in stress and anxiety. In humans, the neuropeptides vasopressin and oxytocin play critical roles in the formation of social attachments. Moreover, altered signaling of these neuropeptide pathways is associated with a decline in the quality of social relationships and with serious illnesses such as autism. Mice, zebrafish, worms and fruitflies do not display social attachments, precluding the use of genetic tools to dissect the neural and molecular networks that mediate these behaviors. Voles, which are small rodents, display striking social bonds such that a mated pair displays enduring co-habitation and sexual fidelity. As in humans, vasopressin and oxytocin are critical for the formation of social ties in voles. Progress in dissecting the neural circuits that mediate social attachment is stymied due to the lack of gene targeting approaches in voles. We propose to develop the reverse genetic strategies in voles that have revolutionized experimental manipulations in the mouse. We propose to develop embryonic stem cells to enable targeted gene knock-out and knock-in experiments in vivo. We will combine these genetic tools with behavioral analysis, high resolution anatomic and functional neural circuit mapping, and systems analysis of signaling to understand how the brain normally generates social attachments. These insights will be applied to understanding how neural circuits malfunction in autism and other mental disorders. Our studies should eventually lead to effective therapies to restore the ability to form enduring social attachments. Public Health Relevance Soc